tbuckley/cabot-search huggingface dataset:
Computational pathology–based HER2 quantification to identify novel biomarkers in gastric cancer (GC).
Authors: Ansh Kapil, Henrik Failmezger, Andreas Spitzmüller, Jessica Chan, Susanne Haneder, Anatoliy Shumilov, Alice Barkell, Toshihiro Oguma, Koichiro Inaki, Fumitaka Suto, John Allard, Jeeyun Lee, J Carl Barrett, Günter Schmidt, Hadassah Sade, Danielle Carroll, Fabiola Cecchi
Journal: Journal of Clinical Oncology (2023)

449 Background: Trastuzumab deruxtecan (T-DXd) is an antibody-drug conjugate (ADC) approved for treatment of HER2-positive GC/gastroesophageal junction adenocarcinoma (GEJA) after chemotherapy (Japan) and for advanced/metastatic GC/GEJA after a trastuzumab-containing regimen (US/Israel/Singapore). Conventional HER2 immunohistochemistry (IHC) scoring identifies potential responders to trastuzumab but may not be suitable for next-generation ADCs capable of bystander killing, such as T-DXd [Modi NEJM 2022]. Use of computational pathology–based tools enables precise and accurate quantification of HER2 expression and spatial analysis, which enables design of better scores to reflect the T-DXd mechanism of action. Methods: Quantitative continuous scoring (QCS) was performed to quantify HER2 expression and distribution per cell in digitized images of HER2-stained (IHC, Ventana 4B5) GC. A QCS-derived signature was identified, called the continuous spatial proximity score (cSPS), which considers spatial location of tumor cells in addition to HER2 expression level and can be used as a surrogate for potential bystander activity. We retrospectively stratified patients in DESTINY-Gastric01 (DG-01; NCT03329690; T-DXd arm: n=123 a ; standard of care [SOC] arm: n=59 a ) using cSPS to give a binary QCS biomarker positive (BM+) or negative (BM−) status. QCS cSPS signature was independently validated on the DESTINY-Gastric02 cohort (DG-02; NCT04014075; n=71 a ). Results: In the DG-01 cohort, enrolled per HER2-positive status by IHC using ASCO/CAP GC scoring guidelines, median progression-free survival (mPFS) was 5.5 a mo with T-DXd and 2.8 a mo with SOC. QCS-derived cSPS scores showed significant survival benefit for BM+ vs BM− in the DG-01 T-DXd arm ( P&lt;0.0001; HR=0.37 [0.24-0.58]) and longer mPFS for BM+ (8.3 mo) vs BM− (3.9 mo). Within the SOC arm, this signature showed the inverse prognosis ( P=0.034; HR=2.17 [1.06-4.44]; mPFS, 2.8 mo for BM+ vs 4.9 mo for BM−), strongly suggesting the signature is predictive of T-DXd response. This signature was validated in the DG-02 cohort (mPFS, 5.5 mo on enrollment by IHC status, 10.1 mo for BM+ vs 3.7 mo for BM−; HR=0.24 [0.13-0.45]; P&lt;0.0001). Conclusions: We established QCS, a novel scoring method for tissue biomarkers. Our validated data and results support possible future use of this quantitative approach against manual scoring for identification of patients with GC who may benefit from T-DXd therapy. Clinical trial information: NCT03329690 , NCT04014075 . [Table: see text]
A cyclic pyrrole-imidazole polyamide reduces pathogenic RNA in CAG/CTG triplet repeat neurological disease models
Authors: Susumu Ikenoshita, Kazuya Matsuo, Yasushi Yabuki, Kosuke Kawakubo, Sefan Asamitsu, Karin Hori, Shingo Usuki, Yuki Hirose, Toshikazu Bando, Kimi Araki, Mitsuharu Ueda, Hiroshi Sugiyama, Norifumi Shioda
Journal: Journal of Clinical Investigation (2023)

Expansion of CAG and CTG (CWG) triplet repeats causes several inherited neurological diseases. The CWG repeat diseases are thought to involve complex pathogenic mechanisms through expanded CWG repeat-derived RNAs in a noncoding region and polypeptides in a coding region, respectively. However, an effective therapeutic approach has not been established for the CWG repeat diseases. Here, we show that a CWG repeat DNA-targeting compound, cyclic pyrrole-imidazole polyamide (CWG-cPIP), suppressed the pathogenesis of coding and noncoding CWG repeat diseases. CWG-cPIP bound to the hairpin form of mismatched CWG DNA, interfering with transcription elongation by RNA polymerase through a preferential activity toward repeat-expanded DNA. We found that CWG-cPIP selectively inhibited pathogenic mRNA transcripts from expanded CWG repeats, reducing CUG RNA foci and polyglutamine accumulation in cells from patients with myotonic dystrophy type 1 (DM1) and Huntington's disease (HD). Treatment with CWG-cPIP ameliorated behavioral deficits in adeno-associated virus-mediated CWG repeat-expressing mice and in a genetic mouse model of HD, without cytotoxicity or off-target effects. Together, we present a candidate compound that targets expanded CWG repeat DNA independently of its genomic location and reduces both pathogenic RNA and protein levels. CWG-cPIP may be used for the treatment of CWG repeat diseases and improvement of clinical outcomes.
Distinct monkeypox virus lineages co-circulating in humans before 2022
Authors: Nnaemeka Ndodo, Jonathan Ashcroft, Kuiama Lewandowski, Adesola Yinka-Ogunleye, Chimaobi Chukwu, Adama Ahmad, David King, Afolabi Akinpelu, Carlos Maluquer de Motes, Paolo Ribeca, Rebecca P. Sumner, Andrew Rambaut, Michael Chester, Tom Maishman, Oluwafemi Bamidele, Nwando Mba, Olajumoke Babatunde, Olusola Aruna, Steven T. Pullan, Benedict Gannon, Colin S. Brown, Chikwe Ihekweazu, Ifedayo Adetifa, David O. Ulaeto
Journal: Nature Medicine (2023)

The 2022 global mpox outbreak raises questions about how this zoonotic disease established effective human-to-human transmission and its potential for further adaptation. The 2022 outbreak virus is related to an ongoing outbreak in Nigeria originally reported in 2017, but the evolutionary path linking the two remains unclear due to a lack of genomic data between 2018, when virus exportations from Nigeria were first recorded, and 2022, when the global mpox outbreak began. Here, 18 viral genomes obtained from patients across southern Nigeria in 2019-2020 reveal multiple lineages of monkeypox virus (MPXV) co-circulated in humans for several years before 2022, with progressive accumulation of mutations consistent with APOBEC3 activity over time. We identify Nigerian A.2 lineage isolates, confirming the lineage that has been multiply exported to North America independently of the 2022 outbreak originated in Nigeria, and that it has persisted by human-to-human transmission in Nigeria for more than 2 years before its latest exportation. Finally, we identify a lineage-defining APOBEC3-style mutation in all A.2 isolates that disrupts gene A46R, encoding a viral innate immune modulator. Collectively, our data demonstrate MPXV capacity for sustained diversification within humans, including mutations that may be consistent with established mechanisms of poxvirus adaptation.
Ppm1d truncating mutations promote the development of genotoxic stress-induced AML
Authors: Monika Burocziova, Petr Danek, Anna Oravetzova, Zuzana Chalupova, Meritxell Alberich-Jorda, Libor Macurek
Journal: Leukemia (2023)

Abstract Hematopoietic stem cells (HSCs) ensure blood cell production during the life-time of an organism, and to do so they need to balance self-renewal, proliferation, differentiation, and migration in a steady state as well as in response to stress or injury. Importantly, aberrant proliferation of HSCs leads to hematological malignancies, and thus, tight regulation by various tumor suppressor pathways, including p53, is essential. Protein phosphatase magnesium-dependent 1 delta (PPM1D) is a negative regulator of p53 and promotes cell survival upon induction of genotoxic stress. Truncating mutations in the last exon of PPM1D lead to the production of a stable, enzymatically active protein and are commonly associated with clonal hematopoiesis. Using a transgenic mouse model, we demonstrate that truncated PPM1D reduces self-renewal of HSCs in basal conditions but promotes the development of aggressive AML after exposure to ionizing radiation. Inhibition of PPM1D suppressed the colony growth of leukemic stem and progenitor cells carrying the truncated PPM1D, and remarkably, it provided protection against irradiation-induced cell growth. Altogether, we demonstrate that truncated PPM1D affects HSC maintenance, disrupts normal hematopoiesis, and that its inhibition could be beneficial in the context of therapy-induced AML.
<i>Notes from the Field</i>: Online Weight Loss Supplements Labeled as Tejocote (<i>Crataegus mexicana</i>) Root, Substituted with Yellow Oleander (<i>Cascabela thevetia</i>) — United States, 2022
Authors: Noah Berland, James Kababick, Cynthia Santos, Diane P. Calello
Journal: MMWR Morbidity and Mortality Weekly Report (2023)
Wastewater Surveillance Data as a Complement to Emergency Department Visit Data for Tracking Incidence of Influenza A and Respiratory Syncytial Virus — Wisconsin, August 2022–March 2023
Authors: Peter M. DeJonge, Carly Adams, Ian Pray, Melissa K. Schussman, Rebecca B. Fahney, Martin Shafer, Dagmara S. Antkiewicz, Adélaïde Roguet
Journal: MMWR Morbidity and Mortality Weekly Report (2023)

Wastewater surveillance has been used to assist public health authorities in tracking local transmission of SARS-CoV-2. The usefulness of wastewater surveillance to track community spread of other respiratory pathogens, including influenza virus and respiratory syncytial virus (RSV), is less clear. During the 2022-23 respiratory diseases season, concentrations of influenza A virus and RSV in wastewater samples in three major Wisconsin cities were compared with emergency department (ED) visits associated with these pathogens. In all three cities, higher concentrations of influenza A virus and RSV in wastewater were associated with higher numbers of associated ED visits (Kendall's tau range = 0.50-0.63 for influenza-associated illness and 0.30-0.49 for RSV-associated illness). Detections of both influenza A virus and RSV in wastewater often preceded a rise in associated ED visits for each pathogen, and virus material remained detectable in wastewater for up to 3 months after pathogen-specific ED visits declined. These results demonstrate that wastewater surveillance has the potential to complement conventional methods of influenza and RSV surveillance, detecting viral signals earlier and for a longer duration than do clinical data. Continued use of wastewater surveillance as a supplement to established surveillance systems such as ED visits might improve local understanding and response to seasonal respiratory virus outbreaks.
Suspected <i>Legionella</i> Transmission from a Single Donor to Two Lung Transplant Recipients — Pennsylvania, May 2022
Authors: Shannon McGinnis, Rebecca J. Free, Jacqueline Burnell, Sridhar V. Basavaraju, Trevor Kanaskie, Elizabeth J. Hannapel, Nottasorn Plipat, Kimberly Warren, Chris Edens
Journal: MMWR Morbidity and Mortality Weekly Report (2023)

In July 2022, the Pennsylvania Department of Health received two reports of laboratory-confirmed Legionnaires disease in patients who had recently received lung transplants from the same donor at a single Pennsylvania hospital. The donor's cause of death was freshwater drowning in a river, raising suspicion of potential donor-derived transmission, because Legionella bacteria naturally live in fresh water. Further investigation of patients receiving other organs from the same donor did not identify additional legionellosis cases. Health care-associated infection caused by water exposure at the hospital was also evaluated as a potential source of infection and was found to be unlikely. Hospital water quality parameter measurements collected during May-June 2022 were within expected ranges and no water disruptions were noted, although no testing for Legionella was performed during this period. Notifiable disease data did not identify any other Legionnaires disease cases with exposure to this hospital within the 6 months before or after the two cases. Although laboratory testing did not confirm the source of recipient infections, available data suggest that the most likely source was the donor lungs. This cluster highlights the need for increased clinical awareness of possible infection with Legionella in recipients of lungs from donors who drowned in fresh water before organ recovery.
Motivating vaccination with financial incentives
Authors: Pol Campos-Mercade, Armando N. Meier, Devin Pope, Florian H. Schneider
Journal: Trends in Cognitive Sciences (2023)

Governments and organizations often offer cash payments for vaccination. How effective are such payments? A literature review shows that incentives usually increase vaccination, especially for nonhesitant populations and when using guaranteed payments. Concerns about negative unintended consequences are unsupported. We also discuss open questions and avenues for future research.
Neuropsychiatric biomarker discovery: go big or go home
Authors: Alicia Ljungdahl, Stephan J. Sanders
Journal: Trends in Molecular Medicine (2023)

Technological advances have enabled high-throughput omics assays, such as parallelized screening of lipids across plasma samples. Pioneering a new paradigm for neuropsychiatric biomarker discovery, Yap et al. describe a large-scale systematic analysis of comprehensive phenotypic, genotypic, environmental, and lipidomic data to unravel the intricate interplay between these and autism-associated traits.
Efficacy, safety, and biomarker analysis of nivolumab in combination with abemaciclib plus endocrine therapy in patients with HR-positive HER2-negative metastatic breast cancer: a phase II study (WJOG11418B NEWFLAME trial)
Authors: Jun Masuda, Hitomi Sakai, Junji Tsurutani, Yuko Tanabe, Norikazu Masuda, Tsutomu Iwasa, Masato Takahashi, Manabu Futamura, Koji Matsumoto, Kenjiro Aogi, Hiroji Iwata, Mari Hosonaga, Toru Mukohara, Kiyoshi Yoshimura, Chiyo K Imamura, Sakiko Miura, Toshiko Yamochi, Hidetaka Kawabata, Hiroyuki Yasojima, Nobumoto Tomioka, Kenichi Yoshimura, Toshimi Takano
Journal: Journal for ImmunoTherapy of Cancer (2023)

Background Hormone receptor (HR)-positive breast cancer is a disease for which no immune checkpoint inhibitors have shown promise as effective therapies. Cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitors synergistically increased the effectiveness of antiprogrammed cell death protein-1 (anti-PD-1)/programmed death-ligand 1 (PD-L1) antibodies in preclinical studies. Methods This non-randomized, multicohort, phase II study evaluated the efficacy and safety of the anti-PD-1 antibody nivolumab 240 mg administered every 2 weeks in combination with the CDK4/6 inhibitor abemaciclib 150 mg twice daily and either fulvestrant (FUL) or letrozole (LET) as a first-line or second-line treatment for HR-positive HER2-negative metastatic breast cancer. The primary end point was the objective response rate (ORR), and secondary end points were toxicity, progression-free survival, and overall survival. Blood, tissue, and fecal samples were collected at multiple points for correlative studies to evaluate immunity biomarkers. Results From June 2019 to early study termination due to safety concerns on July 2020, 17 patients were enrolled (FUL: n=12, LET: n=5). One patient with a prior treatment history in the FUL cohort was excluded. ORRs were 54.5% (6/11) and 40.0% (2/5) in the FUL and LET cohorts, respectively. Treatment-emergent (TE) adverse events (AEs) of grade ≥3 occurred in 11 (92%) and 5 (100%) patients in the FUL and LET cohorts, respectively. The most common grade ≥3 TEAEs were neutropenia (7 (58.3%) and 3 (60.0%) in the FUL and LET cohorts, respectively), followed by alanine aminotransferase elevation (5 (41.6%) and 4 (80.0%)). One treatment-related death from interstitial lung disease occurred in the LET cohort. Ten patients developed liver-related grade ≥3 AEs. Liver biopsy specimens from 3 patients showed hepatitis characterized by focal necrosis with predominant CD8+ lymphocyte infiltration. Marked elevation of tumor necrosis factor-related cytokines and interleukin-11, and a decrease in peripheral regulatory T cells (Tregs), were observed in patients with hepatotoxicity. These findings suggest that treatment-related toxicities were immune-related AEs likely caused by proinflammatory cytokine production and suppression of Treg proliferation due to the addition of abemaciclib to nivolumab therapy. Conclusions Although the combination of nivolumab and abemaciclib was active, it caused severe and prolonged immune-related AEs. Trial registration number JapicCTI-194782, jRCT2080224706, UMIN000036970.
AKT inhibition generates potent polyfunctional clinical grade AUTO1 CAR T-cells, enhancing function and survival
Authors: Vedika Mehra, Giulia Agliardi, Juliana Dias Alves Pinto, Manar S Shafat, Amaia Cadinanos Garai, Louisa Green, Alastair Hotblack, Fred Arce Vargas, Karl S Peggs, Anniek B van der Waart, Harry Dolstra, Martin A Pule, Claire Roddie
Journal: Journal for ImmunoTherapy of Cancer (2023)

AUTO1 is a fast off-rate CD19-targeting chimeric antigen receptor (CAR), which has been successfully tested in adult lymphoblastic leukemia. Tscm/Tcm-enriched CAR-T populations confer the best expansion and persistence, but Tscm/Tcm numbers are poor in heavily pretreated adult patients. To improve this, we evaluate the use of AKT inhibitor (VIII) with the aim of uncoupling T-cell expansion from differentiation, to enrich Tscm/Tcm subsets.VIII was incorporated into the AUTO1 manufacturing process based on the semiautomated the CliniMACS Prodigy platform at both small and cGMP scale.AUTO1 manufactured with VIII showed Tscm/Tcm enrichment, improved expansion and cytotoxicity in vitro and superior antitumor activity in vivo. Further, VIII induced AUTO1 Th1/Th17 skewing, increased polyfunctionality, and conferred a unique metabolic profile and a novel signature for autophagy to support enhanced expansion and cytotoxicity. We show that VIII-cultured AUTO1 products from B-ALL patients on the ALLCAR19 study possess superior phenotype, metabolism, and function than parallel control products and that VIII-based manufacture is scalable to cGMP.Ultimately, AUTO1 generated with VIII may begin to overcome the product specific factors contributing to CD19+relapse.
The evolution of aging and lifespan
Authors: Stacy Li, Juan Manuel Vazquez, Peter H. Sudmant
Journal: Trends in Genetics (2023)

Aging is a nearly inescapable trait among organisms yet lifespan varies tremendously across different species and spans several orders of magnitude in vertebrates alone. This vast phenotypic diversity is driven by distinct evolutionary trajectories and tradeoffs that are reflected in patterns of diversification and constraint in organismal genomes. Age-specific impacts of selection also shape allele frequencies in populations, thus impacting disease susceptibility and environment-specific mortality risk. Further, the mutational processes that spawn this genetic diversity in both germline and somatic cells are strongly influenced by age and life history. We discuss recent advances in our understanding of the evolution of aging and lifespan at organismal, population, and cellular scales, and highlight outstanding questions that remain unanswered.
The African Society of Human Genetics successfully launches global data science workshops
Authors: Victoria Nembaware, Declan Bennett, Emile R. Chimusa, Tinashe Chikowore, Richard Daodu, Valentina Ngo Bitoungui, Scott M. Williams, Segun Fatumo, Sandra Healy, Cathal Seoighe, Ambroise Wonkam, Guida Landouré, Rokhaya Ndiaye, Collet Dandara, Leon Mutesa, Michele Ramsay, Ghada El-Kamah, Giorgio Sirugo, Julie Makani, Khalid Sadki, Mohamed Zahir Alimohamed, Siana Nkya, Amadou Gaye, Raj Ramesar, Ananyo Choudhury, Christian Happi, Nchangwi Syntia Munung, Nadia Kherji, Jade Hotchkiss, Verena Ras, Anita Ghansay, Clarisse Musanabaganwa, Kevin Kum Esoh, Samuel Mawuli Adadey, Simone Christina Coughlan
Journal: Trends in Genetics (2023)
Total recall: the role of PIDDosome components in neurodegeneration
Authors: Pavel I. Volik, Gelina S. Kopeina, Boris Zhivotovsky, Alexey V. Zamaraev
Journal: Trends in Molecular Medicine (2023)

The PIDDosome is a multiprotein complex that includes p53-induced protein with a death domain 1 (PIDD1), receptor-interacting protein-associated ICH-1/CED-3 homologous protein with a death domain (RAIDD), and caspase-2, the activation of which is driven by PIDDosome assembly. In addition to the key role of the PIDDosome in the regulation of cell differentiation, tissue homeostasis, and organogenesis and regeneration, caspase-2, RAIDD and PIDD1 engagement in neuronal development was shown. Here, we focus on the involvement of PIDDosome components in neurodegenerative disorders, including retinal neuropathies, different types of brain damage, and Alzheimer's disease (AD), Huntington's disease (HD), and Lewy body disease. We also discuss pathogenic variants of PIDD1, RAIDD, and caspase-2 that are associated with intellectual, behavioral, and psychological abnormalities, together with prospective PIDDosome inhibition strategies and their potential clinical application.
Avelumab First-line Maintenance for Advanced Urothelial Carcinoma: Analysis from JAVELIN Bladder 100 by Duration of First-line Chemotherapy and Interval Before Maintenance
Authors: Srikala S. Sridhar, Thomas Powles, Miguel Á. Climent Durán, Se Hoon Park, Francesco Massari, Antoine Thiery-Vuillemin, Begoña P. Valderrama, Anders Ullén, Norihiko Tsuchiya, Jeanny B. Aragon-Ching, Shilpa Gupta, Daniel P. Petrylak, Joaquim Bellmunt, Jing Wang, Robert J. Laliberte, Alessandra di Pietro, Nuno Costa, Petros Grivas, Cora N. Sternberg, Yohann Loriot
Journal: European Urology (2023)

In the JAVELIN Bladder 100 phase 3 trial, avelumab first-line maintenance + best supportive care (BSC) prolonged overall survival (OS) and progression-free survival (PFS) versus BSC alone in patients with advanced urothelial carcinoma (advanced UC) without progression after first-line platinum-based chemotherapy. To report post hoc analyses of subgroups defined by the duration of first-line chemotherapy and interval before maintenance. Patients with advanced UC without progression after four to six cycles of platinum-based chemotherapy and a 4–10-wk interval after chemotherapy (n = 700) were randomized to receive avelumab + BSC or BSC alone. Subgroups were defined by duration (quartile [Q]) and estimated number of cycles of chemotherapy, and interval between chemotherapy and maintenance. The median follow-up was >19 mo in both arms. OS (primary endpoint), PFS, and safety were assessed. Hazard ratios (95% confidence interval) for OS with avelumab + BSC versus BSC alone were as follows: by chemotherapy duration—<Q1: 0.65 (0.42–1.02), Q1–Q2: 0.79 (0.50–1.27), Q2–Q3: 0.74 (0.50–1.10), and >Q3: 0.63 (0.39–1.00); by number of cycles—four cycles: 0.69 (0.48–1.00), five cycles: 0.98 (0.57–1.71), and six cycles: 0.66 (0.47–0.92); and by interval—4–<6 wk: 0.75 (0.54–1.04), 6–<8 wk: 0.67 (0.43–1.06), and 8–10 wk: 0.69 (0.47–1.02). Results were similar for PFS. Safety was similar across subgroups. All analyses were exploratory. Post hoc analyses of OS and PFS in subgroups defined by first-line chemotherapy duration and interval before maintenance were generally consistent with the results in the overall population, with similar safety findings. Prospective trials are warranted to confirm these findings. Avelumab maintenance treatment helped patients with advanced urothelial cancer without disease progression after at least four cycles of prior chemotherapy, and who started maintenance treatment at least 4 wk after chemotherapy, to live longer.